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D. Koehn, G. D. Lively, A. Hedberg-Buenz, K. Wang, M. G. Anderson; Identifying QTL Contributing to Murine Central Corneal Thickness. Invest. Ophthalmol. Vis. Sci. 2010;51(13):2155.
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© ARVO (1962-2015); The Authors (2016-present)
Central corneal thickness (CCT) varies widely in humans and is an independent risk factor for primary open angle glaucoma (POAG). Although there is an established association between CCT and POAG, little is known about the biology of this striking health disparity. Our previous work demonstrated that CCT also varies in inbred mouse strains. QTL analysis of an intercross of mice with thin [C57BLKS/J (KS)] and thick [SJL/J (SJL)] corneas identified a significant locus on chromosome 7 (Cctq1), spanning a 20 Mb region. Here, we further examine Cctq1 using congenic mice. We also show evidence for two additional QTL which contribute to CCT through their interaction.
For creation of the low-generation congenic KS.Cctq1SJL strain, KS mice were crossed to SJL to produce F1s. Progeny carrying the SJL alleles at Cctq1 were then backcrossed to KS for four generations. N4 mice were intercrossed and F2 offspring were measured for CCT using ultrasound pachymetry (at 100-120 days). The reciprocal SJL.Cctq1KS congenic was created and measured in the same manner. To identify interacting QTL with the intercross between KS and SJL mice, we performed the scantwo function of R/qtl using the same SNP genotype data that identified Cctq1. Significant interactions were tested through stratified permutation analysis.
KS.Cctq1SJL mice heterozygous for the congenic alleles (i.e., KS/SJL) had an average CCT value of 101.7 +/- 4.3 microns (mean +/- SD; n = 20 eyes). This is significantly higher than inbred KS mice (P<0.05, Student’s t-test). From the two-dimensional QTL analysis, interacting loci were found on chromosomes 11 and 17 (full LOD score = 9.2; P=0.10; suggestive significance).
These results confirm the presence of a QTL on chromosome 7 that contributes to CCT and identify two new interactive QTL. Future efforts will identify the specific CCT gene in the Cctq1 region and the specific interactive genes on chromosomes 11 and 17. We will also extend the QTL approach to identify additional CCT-regulating genes and test roles of these genes in glaucoma.
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